Abstract

Background: Specific mutations in Wnt/β-catenin and mitogen activated protein kinase pathways have been reported to have associations with tumorigenesis of hepatocellular carcinoma (HCC). The clinical implications of CTNNB1 (the coding gene for β-catenin) and BRAF mutations in advanced HCC and their associations with prognosis have not been well studied. Patients and Methods: We reviewed patients with HCC who were screened for enrollment in clinical trials of first-line molecular-targeted therapy for advanced diseases between Mar 2006 and Aug 2009 in a tertiary medical center. Only patients with adequate pathologic specimens obtained at the time of developing advanced disease were included. Direct sequencing of exon 3 of CTNNB1 and exon 15 of BRAF were performed to detect mutations. Associations between the specific mutations and clinicopathologic features or survival of the patients were analyzed. Results: Eighty-one patients were enrolled in the study, with the median age of 56.3 years. Among them, 55 (67.9%) patients were seropositive for hepatitis B virus (HBV) surface antigen; 19 (23.5%) patients were seropositive for antibody against hepatitis C virus (HCV); 77 (95.1%) patients had BCLC stage C; 42 (51.9%) patients had a CLIP score ≤ 3. Missense mutations of CTNNB1 were identified in 10 (12.3%) patients. BRAF mutations were found in 4 (4.9%) patients, including 3 missense and 1 silent mutations. The two gene mutations were mutually exclusive. The median overall survival of patients with and without CTNNB1 mutation were 7.5 and 6.5 months, respectively (P = 0.430). The median overall survival of patients with and without BRAF mutation were 2.8 and 6.6 months, respectively (p = 0.350). CTNNB1 or BRAF mutation had no statistically significant associations with the gender, the ECOG performance status, HBV infection, HCV infection, alpha-fetoprotein levels, prior local treatment, macrovascular invasion, extrahepatic metastasis, BCLC stages, Okuda stages or CLIP scores. Patients with CTNNB1 mutations were more likely to be > 70 years old than patients without CTNNB1 mutations (40% vs. 11.3%, p = 0.017). Conclusions: CTNNB1 and BRAF mutations were relatively rare events in patients with advanced HCC. CTNNB1 mutations were associated with older ages in this specific population (This study was supported by the grant NTUHYLN005).